Dihydroartemisinin-piperaquine effectiveness for seasonal malaria chemoprevention in settings with extended seasonal malaria transmission in Tanzania

Effectiveness of dihydroartemisinin-piperaquine (DP) as seasonal malaria chemoprevention (SMC) was assessed in Nanyumbu and Masasi Districts. Between March and June 2021, children aged 3–59 months were enrolled in a cluster randomized study. Children in the intervention clusters received a monthly, 3-days course of DP for three consecutive months regardless of malaria infection status, and those in the control clusters received no intervention. Malaria infection was assessed at before the first-round and at 7 weeks after the third-round of DP in both arms. Malaria prevalence after the third-round of DP administration was the primary outcome. Chi-square tests and logistic regression model were used to compare proportions and adjust for explanatory variables. Before the intervention, malaria prevalence was 13.7% (161/1171) and 18.2% (212/1169) in the intervention and control clusters, respectively, p < 004. Malaria prevalence declined to 5.8% (60/1036) in the intervention clusters after three rounds of DP, and in the control clusters it declined to 9.3% (97/1048), p = 0.003. Unadjusted and adjusted prevalence ratios between the intervention and control arms were 0.42 (95%CI 0.32–0.55, p < 0.001) and 0.77 (95%CI 0.53–1.13, p = 0.189), respectively. SMC using DP was effective for control of malaria in the two Districts. Trial registration: NCT05874869, https://clinicaltrials.gov/ 25/05/2023.


PR
In the malaria-endemic settings of sub-Saharan Africa underfive children are the most affected by the infection [1][2][3][4] .Most of the malaria-related morbidity and mortality occur during the rainy season 5,6 .Administration of antimalarial chemoprophylaxis to the underfives at appropriate intervals during the rainy season (seasonal malaria chemoprevention (SMC) preferably at the start of the malaria transmission season, up to a maximum of four doses reduces malaria-related morbidity and mortality in the group 6 .The strategy is effective especially in areas where malaria transmission is highly seasonal 7,8 .SMC is recommended in areas where more than 60% of the annual rainfall and 60% of clinical malaria cases occur within 3 and 4 consecutive months 6,8 .In 2012 the World Health Organization (WHO) recommended SMC using sulphadoxine-pyrimethamine (SP) plus amodiaquine (AQ) to children aged 3-59 months 6,[9][10][11] .Since then SMC using SP-AQ has been scaled-up in the Western sub-Sahel region countries 12 , and it has led to a significant reduction in malaria morbidity in the underfives [9][10][11] .Despite its effectiveness in the sub-Sahel region, SP-AQ-SMC cannot be used in East Africa since resistance against both drugs in the combination is common 13 .Instead an effective artemisinin-based combination therapy such as dihydroartemisinin-piperaquine (DP) can probably be used in the region [14][15][16][17] .
Studies show DP to be highly efficacious and well tolerated for treatment of uncomplicated malaria 14,18 .The fast-acting dihydroartemisinin rapidly clears the malaria parasites 19,20 , whereas the long-acting piperaquine with a terminal elimination half-life of 20-30 days, kills the residual parasites and also provides a long posttreatment prophylactic effect 16 .The long DP post-treatment prophylactic effect offers significant benefits over other ACTs 16,17 .In Burkina Faso and Uganda, DP-SMC provided excellent protection against malaria and was well tolerated 15,17,21 .Commonly reported DP adverse events (AEs) include gastrointestinal upset (nausea, vomiting, abdominal pain and diarrhea) as well as dizziness, headache and disturbed sleep.
Tanzania recently adopted SMC strategy using DP in a supplement 2018-2022 Malaria Control Strategic Plan to be used in areas with highly seasonal malaria transmission including Mtwara, and Ruvuma regions 22,23 .No study has however been conducted before to evaluate the protective effectiveness of the strategy in the country before it is scaled out, considering the fact that the targeted settings have extended seasonal malaria transmissions unlike the short seasonal transmissions in the Sahel region.This study therefore, assessed the safety and protective effectiveness of DP when used as SMC in underfive children.

Baseline characteristics of the study participants
A total of 2340 participants with median (inter quartile range) age of 2.25 years (IQR: 1.20-3.43),1215 (51.9) girls and 1635 (69.90%) from Masasi were screened for malaria parasites using both mRDT and microscopy.The participants' baseline characteristics in both arms are presented in     clusters, p < 0.001.But between arms analysis showed that, after the period of three months of SMC administration in the intervention clusters, the proportion of malaria decline was not statistically significantly different between the intervention and control clusters, (p = 0.838).Likewise, although the univariate analysis showed that the intervention clusters had significantly low prevalence of malaria than the control clusters (PR 0.42, p < 0.001), multivariate models which control for other factors indicated that malaria prevalence was 23% lower in the intervention than in the control arm, although the difference was not significant, p = 0.189, Table 3. Distribution of mRDT positivity before and after the three rounds of SMC in the intervention and control clusters by age group and District is presented in Fig. 2. Panels A and B show that the prevalence was higher in the baseline in both arms and decreases substantially in year 2 noticeably in the intervention arm in Masasi District.Furthermore, the analysis for period post intervention (Fig. 2C, D) show that, with exception of the 4 years age group, malaria prevalence in other age groups was significantly lower in the intervention than in the control clusters.Results from a Poisson with wards fitted as random effect and data from year 2019 contributing to the baseline, showed that there was no significant difference between wards randomized to interventions compared to controls (p = 0.427).However, wards which were randomized and received DP intervention in 2021 had significantly lower incidence rate by 3.87% (95%CI 0.3-7.3),p = 0.034, Table 4. Furthermore, malaria incidence was decreasing across the years, it was higher in Nanyumbu District and during the quarters corresponding to rainy seasons particularly April-June when compared to January-March.The significant alpha showed that the random effect model was significantly different from the normal Poisson model.

Effectiveness of the SMC on prevalence of anemia
About 54.00% (1196/2219) of the participants had anemia before the administration of the SMC, and the prevalence was significantly different between the intervention (53.14% (558/1050)) and control clusters (54.62% (638/1168)), x 2 = 0.49, p = 0.485.Following the DP administration, the prevalence of anemia declined to 49.18% (511/1039) in the intervention clusters, whereas in the control clusters it increased to 58.02% (608/1048), and the difference was significant (x 2 = 16.4,p < 0.001).The prevalence of anemia after the SMC administration by age groups and Districts between control and intervention clusters is presented in Fig. 3.In all the age groups, except the age of 2 and 4 years in Nanyumbu District, the prevalence of anemia was significantly lower in the intervention than in the control clusters.

Factors associated with hemoglobin concentration in the study population
Table 5 shows factors associated with hemoglobin (Hb) concentration in the study participants after the intervention.With all factors remaining constant, the mean Hb in the study area was 10.17 g/dL (95%CI 10.06-10.28),www.nature.com/scientificreports/and this was significantly different from zero, p < 0.001.Children with positive mRDT tests had lower Hb by 0.80 g/dL when compared to those with negative tests.The mean Hb concentration was higher by 0.34 g/dL in clusters that received the intervention compared to the controls.On the other hand, an increase in age by one year was associated with an increase in Hb concentration by 0.38 g/dL.Furthermore, the Hb concentration in girls was higher by 0.22 g/dL compared to that of boys, whereas the Hb concentration in Nanyumbu was lower by 0.32 g/dL compared to that of Masasi District.Table 6 shows the prevalence ratios for different variables associated with anaemia which are similar to those presented in Table 5. Clusters randomization at the baseline were shown not to have the impact on the prevalence ratio of cases versus controls (p = 0.430) as well as year of the survey (p = 0.071).Variables that were associated with decrease in prevalence ratio were sex (girls), age, and receiving interventional drug, while mRDT positive individuals and living in Nanyumbu District were associated with increased prevalence ratios, Table 6.

Safety of the SMC
A total of 60 (5.79%) participants had adverse events after the administration of the SMC.In total, 64 AEs were reported, Table 7. Vomiting, fever, and abdominal pain were the major reported AEs, and all were mild and self-limiting.

Discussion
Tanzania recently adopted the SMC strategy for control of malaria in areas with an extended highly seasonal malaria transmission.Therefore, this operational study assessed the safety and protective effectiveness of the strategy using DP in Masasi and Nanyumbu Districts before the scale-out of the strategy.The findings showed that after the three rounds of DP-SMC, malaria prevalence declined significantly in the intervention clusters as shown in the univariate analysis (PR = 0.42, p < 0.001).It was also interesting to note the lower risk of 23% in the intervention when compared to the control, although it was not significant (p = 0.189).The lack of significance can be attributed to the low statistical power due to lower effect of the intervention as a result of lower compliance to SMC delivery in all the three rounds.The DP coverage in the first round was above 60%, however, it declined to 45% and 35% in the second and third rounds, respectively.The study was conducted during the COVID-19 pandemic.The first round of DP delivery was conducted in early March 2021 before the country had adopted the time, the study population perceived DP delivery to be used to also deliver COVID-19 vaccine, and therefore, refused to take the medicine.This negatively affected the SMC coverage and hence its effect.Furthermore, when assessed by age group, in all the age groups except in the year 4 group in Nanyumbu District malaria prevalence was significantly lower in the intervention than in the control clusters (Fig. 2C, D).Similar findings have been reported in the Sahel countries [9][10][11]15 . Howver, when comparing malaria prevalence between the year 2020 and 2021 (before and after three rounds of DP), both in the control and intervention clusters the malaria prevalence was lower in the 2021 than 2020 in all the age groups and both Districts.Likewise, malaria incidences declined significantly both in the control and intervention clusters between 2020 and 2021.However, there was no significant difference in malaria incidences when compared between the control and intervention clusters in 2021 after the three rounds of DP in the intervention clusters.The corresponding decline of malaria prevalence and incidences in the control clusters similar to intervention clusters may be due to different factors especially weather driven factors which may have affected all of the study arms 24,25 .Clusters were randomized to ensure an evenly distribution of control and intervention clusters in the study Districts, with evaluation villages/sites been selected in such a way that there was buffer zones to prevent contamination from adjacent villages/wards with different intervention.Thus, probably climatic factors that influence mosquito bleeding and hence malaria transmission such as decreased rainfall and temperature change out of the optimal range may have contributed to the decline of malaria in both arms.On the other hand, low DP-SMC coverage in the intervention clusters may have probably led to the lack of significant difference in malaria incidences between the intervention and control clusters.
Anemia is one of the major complications of malaria infection [26][27][28] .At the baseline more than half of the study children had anemia, and was not statistically significantly different between arms.After the three rounds of SMC, the anemia prevalence declined significantly in the intervention clusters, and increased significantly in the control clusters.Analysis by age groups showed that with the exception of the age groups of 2 and 4 years in Nanyumbu District, anemia prevalence was significantly lower in the intervention than in the control clusters.Studies in other settings have also shown a significant decline of anemia prevalence after the SMC intervention [9][10][11] .However, in this study it is not clear why in the control clusters although the malaria prevalence declined significantly but the anemia prevalence increased.Nonetheless, in this study factors including having malaria infection and residing in Nanyumbu District were positively associated with anemia, whereas, sex especially female, increasing age, and having received the DP-SMC were negatively associated with anemia.
The DP-SMC was safe and well tolerated.Only 6.0% of the participants in the intervention clusters had adverse events.Vomiting, fever and abdominal pain were the adverse events reported most frequently.All the adverse events were mild and self-limiting.Similar findings have been observed in other studies 14,15 .
Despite its strength the study had limitations.The study did not quantify the effect of climatic factors on malaria transmission and prevalence during the study period.This would have aided in understanding the effect of SMC alone on malaria prevalence.Furthermore, low coverage/distribution of DP in all the three rounds might have contributed to low impact of DP observed in this study.

Conclusion
The DP was safe and effective for using as SMC for control of malaria in Masasi and Nanyumbu Districts.The observed adverse events were mild and self-limiting.The drug can therefore, be used in settings of Tanzania with extended seasonal malaria transmission to reduce the burden of malaria.

Study area
The study was conducted in rural settings of Nanyumbu and Masasi Districts, Mtwara region.Nanyumbu District has 14 wards, and Masasi District has 22 wards.The Districts had a projected population of 82,740 children aged

A total of 20 Figure 1 .
Figure 1.Trial profile showing study population screening for malaria using mRDT tests, test results (mRDT positive (+ve) and negative (−ve)) and population that received study drug (DP) at the three time points.

Figure 2 .
Figure 2. Distribution of mRDT positivity by age group.The top panels show the prevalence in the control and intervention groups before and after deployment of DP in Masasi (A) and Nanyumbu (B) Districts.Panels C (Masasi) and D (Nanyumbu) shows the prevalence of mRDT positive in 2021 by study group (control vs. intervention).

Table 1 .
. The children in the intervention and control clusters had statistically significantly different median age, mean weight, mean height, mean body Characteristics of the participants in the intervention and control clusters at baseline.Significant values are in italics.

Table 4 .
Factors associated with risk of malaria among patients who attended at the outpatient clinics in Nanyumbu and Masasi Districts between 2019 and 2021.

Table 5 .
Multivariable model showing factors associated with haemoglobin concentration among the study participants.

Table 6 .
Multivariable COVID-19 vaccines as a measure to control the pandemic.The government of Tanzania officially approved the use of vaccines against COVID-19 on 31st March 2021, just before the delivery of the second and third rounds of DP, in April and May 2021.Due to population skepticism and misconceptions around the COVI-19 vaccines at model showing prevalence ratios (PRs) of different variables associated with anaemia (Hb < 11 g/dl) in the study area.Vol.:(0123456789) Scientific Reports | (2024) 14:2143 | https://doi.org/10.1038/s41598-024-52706-zwww.nature.com/scientificreports/

Table 7 .
Distribution of the adverse events after administration of SMC in Nanyumbu and Masasi Districts.Significant values are in bold.